Jump to

Abstract

Aldosterone and Akt signaling both play pivotal roles in the pathogenesis of heart failure; however, little is known about the interaction between them. Here we hypothesized that in cardiomyocytes, aldosterone would provide a time-dependent biphasic activation of Akt-GSK3β signaling. To test this, neonatal rat cardiomyocytes (NRCM) were stimulated with aldosterone and assessed the phosphorylation of Akt (Ser 473) and GSK3β (Ser 9). Short-term stimulation within 10 minutes transiently increased Akt-GSK3β phosphorylation and the action disappeared at 20 minutes. However, the phosphorylation were again increased after 24 hours of stimulation, which would be an unfavorable reaction due to chronic Akt activation as we have previously shown. Moreover, we found that these effects were observed only under a high glucose condition (25mM or 40 mM) but not under a normal glucose condition (5.5 mM) and that the former action was not blocked but the latter was blocked by eplerenone, a mineralocorticoid receptor (MR) inhibitor. In contrast, the former action was blocked by PI3K inhibitor or Na+/H+ exchanger (NHE) inhibitor. These results suggest that the acute activation of this pathway would be envisaged as a novel non-genomic glucose-sensitive cascade of aldosterone through NHE1, PI3K and Akt. To examine the significance of this rapid action of aldosterone on cell viability, NRCM were exposed to hydrogen peroxide for 30 minutes. A short-term aldosterone stimulation significantly rescued NRCM from oxidative stress-induced cellular damage (cell viability, % of control; 79.5±2.8% with aldosterone vs 69.9±2.4% without aldosterone, n=6, p<0.02). Of note, eplerenone did not abrogate this beneficial effect, while a PI3K inhibitor did. In conclusion, aldosterone has a novel non-genomic action on glucose-sensitive Akt signaling in cardiomyocytes, which would be a physiological compensatory mechanism for the efficient use of glucose in heart failure. However, its superfluous activity would have adverse impacts on cardiomyocytes by excess activation of Akt in a chronic MR-dependent genomic manner. These results further emphasize the usefulness of MR inhibitors for suppressing the unfavorable genomic action without blocking out the favorable non-genomic action.